Device for assessment and therapy of temporal ventricular desynchronization

ABSTRACT

A device includes a hemodynamic sensor measuring blood flow in the left chambers of a myocardium, at least one motion sensor measuring a displacement of the walls of the left ventricle of the myocardium, a first analysis module determining a time of closure of the aortic valve based on a signal of the hemodynamic sensor, a second analysis module determining a time of peak contraction of the left ventricle based on a signal from the motion sensors, and a third analysis module determining a time between the moment of peak contraction of the left ventricle and the moment of closure of the aortic valve. If the peak of contraction of the left ventricle is after the instant of closure of the aortic valve, the device adjusts the inter-ventricular delay and/or the atrioventricular delay to minimize or cancel the time disparity.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/042,385, filed Sep. 30, 2013, which claims the benefit of andpriority to French Application No. 1259252, filed Oct. 1, 2012, both ofwhich are hereby incorporated by reference herein in their entireties.

BACKGROUND

The present disclosure relates generally to medical devices for use inpatient care. The present disclosure relates more particularly to amedical device for the diagnosis and treatment of ventriculardesynchronization in a patient.

Ventricular desynchronization is a heart condition that typically occursin two forms: (1) spatial desynchronization and (2) temporaldesynchronization. Spatial desynchronization and temporaldesynchronization may occur independently or in combination with eachother.

In spatial desynchronization, a cardiac conduction disorder causes adelay in the contraction of one of the heart ventricles (i.e., the leftventricle or the right ventricle) relative to the contraction of theother ventricle, leading to deterioration in the hemodynamic status ofthe patient. U.S. Patent Application Publication No. 2005/0027320 A1(granted as U.S. Pat. No. 7,092,759) discloses a device for thedetection of the desynchronization between the two ventricles (i.e.,spatial desynchronization). The disclosed device allows for theassessment and application of an appropriate stimulation therapy,including the optimization of the interventricular delay (VVD).

Temporal desynchronization is characterized by a late contraction of allor part of the left ventricle in relation to the closure of the aorticvalve. In temporal desynchronization, some segments of the ventricularwall are still in a contracted state during the diastolic phase (i.e.,after the ejection of blood into the aorta, during the closing of theaortic valve) and, in extreme cases, after the opening of the mitralvalve, (i.e., at the beginning of the phase of passive filling of theleft ventricle with blood from the left atrium). Temporal ventricularsynchronization may be characterized by the presence of diastoliccontraction (i.e., with setback) of some segments of the left ventriclewith an antagonistic effect on the hemodynamic activity and a decreasein ejection fraction, considered the reference hemodynamic parameter.

These ventricular desynchronizations can be treated by a CardiacResynchronization Therapy (CRT) or Bi-Ventricular Pacing (BVP) techniqueconsisting of implanting a device with electric leads (i.e., electrodes)in the patient to stimulate one or both ventricles at variousventricular locations. The device applies an appropriateinterventricular delay (VVD) between the respective moments ofstimulation of the right and left ventricles. The VVD may be adjusted toresynchronize the contraction of the ventricles with fine tuning of thepatient's hemodynamic status. The VVD can be zero, positive (i.e., theleft ventricle being stimulated after the right ventricle) or negative(i.e., the right ventricle being stimulated after the left ventricle).

Various global assessment techniques of hemodynamic function in apatient are known. For example, European Patent Application PublicationNo. 1108446 A1 (ELA Medical S.A.) evaluates hemodynamic function usingan intracardiac bio-impedance measurement. The intracardiacbio-impedance measurement is a parameter indicative of the cardiacoutput and thus of the ejection fraction. Another example is provided inEuropean Patent Application Publication No. 2092885 A1 (Sorin CRMS.A.S), which extracts information from an endocardial accelerationsignal and combines various indicators representative of the patient'shemodynamic status. However, these devices operate a non-specificdiagnosis of ventricular desynchronization, without distinction betweentemporal and spatial desynchronization.

International Publication No. WO 95/27531 A1 discloses a device,provided in particular with one or more velocity or acceleration sensorsmeasuring the displacement of the heart wall in order to determinewhether myocardial contractions are occurring. The sensor can be anendocardial acceleration (EA) sensor which produces a signal reflecting,in the form of two peaks, the two heart sounds produced by the closingof the mitral valve and at the opening of the aortic valve. Measuringthe height of one or the other peak of the EA signal provides anindication of whether any mechanical activity of the heart is occurring.In the absence of mechanical activity of the heart, the device issues anappropriate bradycardia therapy (e.g., conventional stimulation of theDDD or DDI type). However, in the presence of a mechanical activity,therapy is inhibited so as not to interfere with the spontaneouscontractions of the myocardium.

U.S. Pat. No. 7,212,861 and European Patent Application Publication No.2495013 describe various techniques for search of an optimal stimulationconfiguration based on the detection of the mechanical activity of theventricle. However, like the documents, they do not consider thespecific diagnosis or treatment of any possible ventriculardesynchronization.

Current treatments and devices do not provide a specific method todiagnose the temporal desynchronization of the ventricle, regardless ofany consideration relating to possible spatial desynchronization. Inparticular, current treatments and devices do not distinguish betweentemporal and spatial desynchronization or apply differentiated therapiesaccording to the type of disorder. While it is generally sufficient toapply biventricular pacing with VVD (e.g., as described in U.S. PatentApplication Publication No. 2005/0027320 A1) to address spatialdesynchronization, the treatment of temporal desynchronization—whichinvolves only one ventricle—may require a much finer adjustment ofvarious stimulation parameters. The stimulation parameters may include,for example, the atrioventricular delay (AVD) and/or a combination ofAVD and VVD. The specific detection of a temporal desynchronization mayhelp to treat, or possibly even cure, a disorder which is untreated orinadequately treated by conventional CRT therapy.

OBJECT AND SUMMARY

The present invention relates to a device for evaluating and treatingventricular desynchronization in a patient. The device includes ahemodynamic sensor for delivering a signal representative of blood flowin the left cavities of the myocardium, at least one motion sensor fordelivering a signal representative of a displacement of the walls of theleft ventricle of the myocardium, a first analysis means for determininga closing moment of the aortic valve based on the signal of thehemodynamic sensor, a second analysis means for determining acontraction peak moment of the left ventricle based on the signal(s) ofthe motion sensor(s), and a third analysis means for determining therelative temporal position of the moment of the contraction peak of theleft ventricle relative to the aortic valve closing moment.

The hemodynamic sensor may be at least one of an implantable or externalendocardial acceleration sensor, an implantable bioimpedance sensor, animplantable or external T wave detection sensor, and an implantableventricular pressure sensor.

The motion sensor may be at least one of a motion sensor implantable inan endocardial, epicardial or endocoronary site, an external motionsensor, and a field tomography signal collection sensor.

In some embodiments, the implantable hemodynamic sensor is a sensor fordelivering an endocardial acceleration (EA) signal. The first analysismeans may be means for isolating a component (EA2) of the EA signal. Theisolated signal component EA2 may correspond to the second peak ofendocardial acceleration associated with the ventricular isovolumetricrelaxation over a cardiac cycle between two successive ventricularevents. In some embodiments, the beginning of the EA2 signal componentmay be used as the moment of closure of the aortic valve. In someembodiments, the moment of closure of the aortic valve may be determinedby identifying a moment at which an energy envelop based on the EA2signal component crosses an energy threshold.

In some embodiments, the device of the invention can also be used fortherapy of temporal ventricular desynchronization. To treat temporalventricular desynchronization, the device may include a bi-, tri- ormultiventricular stimulation means for delivering stimulation pulses toelectrodes respectively located in at least one right ventricular pacingsite and in at least one left ventricular pacing site. The stimulationpulses may be delivered according to a current stimulation configurationwith application of a modifiable interventricular delay VVD and/or amodifiable atrioventricular delay AVD. If the third means of analysisdetermines that the moment of the peak contraction of the left ventricleis posterior to the moment of closure of the aortic valve, then the VVDand/or the AVD of the current stimulation configuration can be adjustedto reduce or cancel the delay of the peak of contraction of the leftventricle after the closure of the aortic valve.

In some embodiments, the device can be used to diagnose and treat bothtemporal ventricular desynchronization and spatial ventriculardesynchronization. For example, the device may include at least twomotion sensors for delivery of signals representative of the respectivedisplacements of the walls of the right and left ventricles of themyocardium. The second analysis means may determine the moments of therespective contraction peaks of the left and right ventricles. Thedevice may include a means for assessing the spatial ventriculardesynchronization means in the patient by determining a concomitancedefect in the respective contraction peaks of the left and rightventricles.

For treating the spatial desynchronization thus diagnosed, the devicemay include a bi-, tri- or multiventricular pacing means for deliveringstimulation pulses to be respectively applied to electrodes implanted inat least one right ventricular stimulation site and in at least one leftventricular stimulation site. The stimulation pulses may be deliveredaccording to a current stimulation configuration with application of amodifiable interventricular delay VVD and/or a modifiableatrioventricular delay AVD. If the means for assessing the temporaldesynchronization determine that the moments of the contraction peaks ofthe left and right ventricles are both posterior to the moment ofclosure of the aortic valve, the VVD and/or the AVD of the currentstimulation configuration can be changed and in a direction that reducesand cancels the delay of these two contraction peaks after closure ofthe aortic valve and/or reduces the temporal gap between these twocontraction peaks.

DRAWINGS

Further features, characteristics and advantages of the presentinvention will become apparent to a person of ordinary skill in the artfrom the following detailed description of preferred embodiments of thepresent invention, made with reference to the drawings annexed, in whichlike reference characters refer to like elements and in which:

FIG. 1 is a drawing of a heart showing heart chambers and the associatedvalves, according to an exemplary embodiment.

FIG. 2 illustrates a heart paired with various leads equipped withhemodynamic and motion sensors, according to an exemplary embodiment.

FIG. 3 is a series of graphs illustrating four different characteristicsignals that can be collected during a cardiac cycle, according to anexemplary embodiment.

FIG. 4 shows in more detail the shape of the endocardial accelerationsignal over a given cycle, with the various temporal markers used by theinvention, according to an exemplary embodiment.

FIG. 5 is a representation in an echocardiographic diagram of a typicalsituation of temporal desynchronization of the left ventricle, accordingto an exemplary embodiment.

FIG. 6 is a series of four graphs illustrating a typical situation ofdual, temporal and spatial, desynchronization of the ventricles,according to an exemplary embodiment.

FIG. 7 is a flow chart of a process for diagnosis and treatment oftemporal ventricular desynchronization according to an exemplaryembodiment.

DETAILED DESCRIPTION

The present invention relates to systems and methods for evaluating andtreating temporal ventricular desynchronization. The systems and methodsdescribed herein may be used to control an implantable device (e.g., acardiac pacemaker or a defibrillator/cardioverter, etc.) based onsignals collected by the device (e.g., via endocardial leads and/or oneor more implanted sensors) for the evaluation and therapy of temporalventricular desynchronization.

The present invention may particularly be applied to implantable devicessuch as those of the Reply and Paradym device families produced andmarketed by Sorin CRM, Clamart France, formerly known as ELA Medical,Montrouge, France. These devices generally include programmablemicroprocessor circuitry configured to receive, format, and processelectrical signals. The electrical signals may be collected (e.g.,detected) by implanted electrodes in communication with the devices. Thedevices are configured to deliver stimulation pulses to the electrodes.It is possible to transmit (e.g., by telemetry) software that will bestored in a memory of the implantable devices and executed to implementthe functions of the invention that will be described herein. Theadaptation of these devices to implement the functions and features ofthe present invention is believed to be within the abilities of a personof ordinary skill in the art, and therefore will not be described indetail.

The systems and methods described herein may use a device that is thesame or similar to the device described in International Publication No.WO 95/27531 A1, incorporated by reference herein in its entirety. Forexample, the device may include an hemodynamic sensor delivering asignal representative of a blood flow in the left chambers of themyocardium; at least one motion sensor delivering a signalrepresentative of a displacement of the walls of the left ventricle ofthe myocardium; first analysis means for determining a moment of closureof the aortic valve from the signal of the hemodynamic sensor; secondanalysis means for detecting and evaluating a contraction peak of theleft ventricle from signal(s) of the motion sensor(s); and bi-, tri- ormultiventricular stimulation means for delivering stimulation pulses tobe applied to electrodes located respectively in at least one rightventricular pacing site and in at least one left ventricular pacingsite. The stimulation pulses may be applied according to a currentstimulation configuration with application of at least one modifiableinter-ventricular delay VDD and/or one modifiable atrioventricular delayAVD.

In some embodiments, the second analysis means determines a timing ofsaid peak of contraction of the left ventricle. In some embodiments, thedevice further includes a third analysis means for the measure of atemporal shift between the instant of the peak of contraction of theleft ventricle and the instant of closure of the aortic valve. Thedevice may further include means to change the VVD and/or AVD or thecurrent stimulation configuration in a direction reducing and cancelingthe delay of the peak of contraction of the left ventricle after closureof the aortic valve. The stimulation configuration may be changed if thethird analysis means determines that the instant of the peak of the leftventricular contraction is later than the instant of closure of theaortic valve.

The method of the invention is primarily implemented by software means,using appropriate control methods (e.g., processes, algorithms,techniques, etc.) executed by a microcontroller or a digital signalprocessor. For the sake of clarity, the various processing steps will bedecomposed and schematized by a number of distinct functional blocks.However, this representation is merely illustrative. In someembodiments, the various functions (e.g., data collection, signalprocessing, output generation, etc.) may be implemented by one or moresoftware modules within the implant and/or the external device.

Referring now to FIG. 1, an illustration of the cavities and valves ofthe heart 10 are shown, according to an exemplary embodiment. Heart 10is shown to include a right atrium 12, a right ventricle 14, a leftatrium 16, and a left ventricle 18. Mitral valve 20 (i.e., anatrioventricular valve) is located between the left atrium 16 and theleft ventricle 18. Aortic valve 24 (i.e., a semilunar valve) is locatedbetween the left ventricle 18 and the aorta 22.

In some embodiments, the systems and methods of the present inventionare capable of monitoring changes in blood flow in the left cavities(i.e., left atrium 16 and left ventricle 18), the wall motions of theleft ventricle 18, and/or the movements of the wall of the rightventricle 14.

Referring now to FIG. 2, heart 10 can be monitored by various sensorsconnected to heart 10 by leads. These leads may be endocardial leadsintroduced into the right atrium 12 and/or the right ventricle 14,epicardial leads attached to the outer wall of the myocardium, orendocoronary leads arranged vis-à-vis the left cavities. The leads maybe introduced into a vein 26 of the coronary venous system via thecoronary sinus 28 opening into the right atrium 12.

In some embodiments, one or more of the leads connect to a hemodynamicsensor. The hemodynamic sensor may provide a signal representative ofchanges in blood flow at the time of closure of the aortic valve 24. Insome embodiments, the sensor may be arranged, for example, on anendocardial lead 30 terminating at the apex of the ventricle 14 (i.e.,sensor 32) and configured to sense an endocardial acceleration (EA).

The one or more leads may include an atrial lead 34. Atrial lead 34 maybe connected to an endocardial acceleration sensor 36 placed against thewall of the right atrium 12. An EA sensor may include, for example, anaccelerometer integrated into the head of an endocardial lead, asdescribed in European Patent Application Publication No. 0515319 A1(Sorin Biomedica Cardio SpA).

In some embodiments, the hemodynamic sensor includes an external EAsensor placed on the patient's thorax, an intracardiac bioimpedanceimplantable sensor, an implantable or external sensor for detection ofthe T-wave of the electrocardiographic signal, and/or a ventricularpressure implantable sensor. These additional sensors may be included inaddition to or in place an EA sensor integrated into an endocardiallead.

In some embodiments, the device includes a motion sensor configured todeliver a signal representative of a displacement of the walls of theleft ventricle 18. The motion sensor may be placed, for example, on anendocoronary lead 38 at one or more locations 40 disposed against thewall of the left ventricle 18. Alternatively or in addition, it ispossible to use an epicardial lead 42 equipped with an end sensor 44placed against the wall of the left ventricle 18.

In some embodiments, the device includes an epicardial lead 46 equippedwith an end sensor 48 attached to an outer wall of the right ventricle14. Sensor 48 may be used to measure the motion of the right ventricle.

In some embodiments, the device uses multiple motion sensors placed indifferent parts of the wall of the left ventricle 18 in order to moreprecisely analyze the movements of the different segments of the leftventricular wall. These various sensors can be placed on the same lead(e.g., endocoronary lead 38) or on different leads (e.g., endocoronarylead 38 and epicardial lead 42, etc.).

In some embodiments, various alternative techniques can be used toobtain a representation of the motion of the walls of the left ventricle18. For example, the device may use electrotomographic analysis asdescribed in U.S. Patent Application Publication No. 2008/0183072 A1,incorporated by reference herein for its description thereof.

The basic idea of the invention is to obtain an indication of the timeof closure of the aortic valve. As described in greater detail below,the time of closure of the aortic valve may be obtained from the signalrepresentative of the flow of blood in the left cavities delivered bythe hemodynamic sensor. The time of closure of the aortic valve may beused as a reference marker for the diagnosis of temporalsynchronization. For example, the reference marker (i.e., defined by thetime of closure of the aortic valve) may be compared with the signaldelivered by the motion sensor of the left ventricle to determinewhether or not there is a state of contraction of the left ventricleposterior to this temporal marker. If so, temporal ventriculardesynchronization may be diagnosed and appropriate measures can be takenafter the diagnosis in an attempt to reduce or eliminate thispathological phenomenon.

Referring now to FIGS. 3 and 4, a method to determine the time ofclosure of the aortic valve will now be explained. Referringspecifically to FIG. 3, several different signals characterizing theactivity of the heart during a cardiac cycle are shown, according to anexemplary embodiment. FIG. 3 is shown to include a profile ofintracardiac pressures P_(A), P_(VG) P_(OG). The characteristic P_(A)corresponds to the aortic pressure, P_(VG) corresponds to leftventricular pressure, and P_(OG) corresponds to left atrium pressure.Pressures P_(A), P_(VG), P_(OG) vary as heart 10 goes through thefollowing phases: A (contraction of the left atrium), MC (closure of themitral valve), AO (opening of the aortic valve), AC (closure of theaortic valve), and MO (opening of the mitral valve).

FIG. 3 is shown to further include a graph of surface electrocardiogram(ECG) with the P wave corresponding to the depolarization of the atria,the QRS complex corresponding to the depolarization of the ventricles,and the T wave corresponding to the ventricular repolarization.

FIG. 3 is shown to further include a collected endocardial acceleration(EA) signal and a signal LVW from a motion sensor. The endocardialacceleration signal EA forms two main components in a given cardiaccycle, corresponding to the two major heart sounds (e.g., S1 and S2sounds of the phonocardiogram). It is possible to recognize eachcomponent in the cardiac cycle. The signal LVW of the motion sensorrepresents the displacements of the left ventricular wall. Signal LVWhas a peak (P_(L)) marking the end of the contraction of all segments ofthe left ventricle.

Referring specifically to FIG. 4, the variations of the EA signal duringa cardiac cycle are more precisely illustrated, according to anexemplary embodiment. The EA signal is shown to include an EA1 componentand an EA2 component. The EA1 component begins after the QRS complex andis caused by a combination of the closing of the atrioventricular valves(i.e., the mitral and tricuspid valves), the opening of the semilunarvalves (i.e., aortic and pulmonary valves) and the contraction of theleft ventricle. The EA2 component occurs during the phase ofisovolumetric ventricular relaxation. The EA2 component accompanies theend of ventricular systole and is mainly produced by the closing of theaortic and pulmonary valves.

A characteristic temporal marker correlated with the closure of theaortic valve can be extracted from the EA signal shown in FIGS. 3 and 4.Specifically, the temporal marker can be extracted from the EA2component shown in FIG. 4. The characteristic temporal marker maycorrespond to a time indicated by the dotted line labeled AC in FIG. 3.

Analysis of the EA signal is preferably determined by averaging the EAsignal over several cycles (e.g., typically three to five cycles). TheEA signal may be analyzed and/or averaged using the technique describedin European Patent Application Publication No. 2092885 A1 (ELA Medical),incorporated by reference herein for its description thereof. Such atechnique may be useful for eliminating cycle-by-cycle variations intime by readjusting the successive components before averaging.

In some embodiments, the EA signal is continuously collected. The EAsignal may be processed by cutting (e.g., splitting, dividing, etc.) theEA signal into sub-signals. Each sub-signal may correspond to theduration of a cardiac cycle and may be identified by cycle start markers(e.g., marking a beginning of the cardiac cycle) for performing thecutting. The temporal markers of the start cycle can be provided by theimplanted device which, according to the operating mode, stores themoments of V stimulation or the moments of detection of the R wave.

Processing the EA signal may further include segmenting each of thesub-signals to individualize the EA1 and EA2 components in a giventemporal window. For each of the components EA1 and EA2, processing mayinclude searching for a correlation peak relative to the EA1 or EA2components of the other collected cycles, calculating a temporal offset,and applying the calculated temporal offset to the current EA1 or EA2component. Applying the temporal offset may align the EA1 or EA2component with respect to the other. The analysis processing of the EAsignal can then be run on the successive EA1 and EA2 components, withelimination of the bias cycle to cycle variability through thispre-processing.

In some embodiments, processing the EA signal includes determining thestart time T_(stEA2) of the EA2 component. Start time T_(stEA2) can beobtained, for example, by thresholding an energy envelope (e.g., shownas a dashed line in FIG. 4). The energy envelope may be obtained bysquaring the value of the signal samples and applying a smoothing window(e.g., 100 ms) to smooth the energy envelope. The time T_(stEA2) may beidentified by comparing the magnitude of the energy envelope to athreshold value. The threshold value may correspond to approximately 10%of the maximum energy associated with the EA2 component.

Referring now to FIG. 5, various parameters of a typical temporaldesynchronization pathology of the left ventricle are shown, accordingto an exemplary embodiment. FIG. 5 shows an echocardiographic chart withseveral timing diagrams. The timing diagrams are shown to include an ECGsignal marking the start of the atrial contraction, a left pre-ejectionphase LPEP showing the aortic flow AF, a right pre-ejection phase RPEPshowing the pulmonary flow PF, a phase of post-discharge with the E wavecorresponding to the passive filling and the A wave corresponding to thecontribution to filling of the atrial contraction, and LVW and RVWsignals respectively delivered by the motion sensors of the walls of theleft ventricle and the right ventricle.

The end of the flow of blood into the aorta (i.e., the end of the AFflows, marked by dashed line AC) marks the completion of the systolicphase SYS. The end of the flow of blood into the aorta also marks thebeginning of the diastolic phase DIAS, after closure of the aortic valveat time AC.

The last two timing diagrams LVW and RVW have respective peaks P_(L) andP_(R.) In FIG. 5, peaks P_(L) and P_(R) are concurrent, which means thatthe walls of the left ventricle and of the right ventricle completetheir contraction at the same time. When P_(L) and P_(R) are concurrent,there is no spatial desynchronization. However, FIG. 5 shows a temporaldesynchronization, since the peaks P_(L) and P_(R) (which mark the endof the contraction of the ventricles) are after the closure of theaortic valve AC. Ideally, peaks P_(L) and P_(R) should be concurrentwith this closure, with a delay ΔT.

Still referring to FIG. 5, an overlap phenomenon OVL is shown. Theoverlap exists to the extent that ventricular contraction peaks P_(L)and P_(R) are after the time of opening of the mitral valve MO. Whenpeaks P_(L) and P_(R) occur after the opening of the mitral valve, thecontraction of the ventricles encroaches on the passive filling of theventricle E. In FIG. 5, peaks P_(L) and P_(R) occur at the wrong time(i.e., too late) compared to the normal hemodynamic behavior. In otherwords, the normal systolic contraction Ø1 of the left ventricle isextended by a pathologic diastolic contraction Ø2, which should bediagnosed and treated to restore proper functioning of the heart,particularly from the hemodynamic point of view.

Referring now to FIG. 6 another representation of a situation ofventricular desynchronization is shown, according to an exemplaryembodiment. FIG. 6 shows the Endocardial acceleration EA, theelectrocardiogram ECG, and the LVW and RVW signals representative of themovements of the walls of the respective left and right ventricles.

FIG. 6 illustrates both a temporal desynchronization and a spatialdesynchronization. The temporal desynchronization is evident by thedelay ΔT between the peak of the LVW signal and the second peak EA2 ofthe EA signal. The second peak EA2 of the EA signal corresponds to theclosure of the aortic valve AC. The spatial desynchronization ΔL/R isevident by the relative shift of the peaks LVW and RVW. As shown in FIG.6, the contraction of the right ventricle (i.e., the peak of RVW) islater than that of the left ventricle (i.e., the peak of LVW).

Referring now to FIG. 7, a flowchart illustrating the various steps of amethod for the diagnosis and treatment of temporal ventriculardesynchronization is shown, according to an exemplary embodiment. At theimplantation of the device or at a later follow-up visit to thephysician (step 50), the device sets a test matrix with differentcombinations of possible atrioventricular (AVD) and interventricular(VVD) delays (step 52).

In steps 54-60, the device tests various combinations of AVD and VVDvalues. The device is programmed with each of these pairs of delays{AV_(i), VV_(j)} (step 54). The device applies a pair of values andmeasures the corresponding time T_(stEA2ij) (representative of theclosing time of the aortic valve AC) and the time of the contractionpeak (representative of the moment when all segments of the leftventricle wall have finished contracting) (step 56). The collectedvalues are stored (step 58) and the device passes to the following pairof set values (step 60). Steps 54-60 may be repeated until all pairs ofvalues {AV_(i), VV_(j)} in the test matrix have been programmed andtested.

Once all the pairs of values in the test matrix have been tested, thedevice selects the pair among these pairs of values that minimizes thetemporal difference between the reference marker T_(stEA2ij) and thecontraction peak of the left ventricle (step 62). Ideally, the deviceselects the pair of values that completely eliminates the temporaldifference between the reference marker T_(StEA2ij) and the contractionpeak of the left ventricle.

The combination of AVD and VVD that provide the minimal temporaldifference between the reference marker T_(stEA2ij) and the contractionpeak of the left ventricle may represent the best condition of temporalresynchronization. A minimum difference that is slightly positive orzero indicates that it can be expected that all segments, or virtuallyall segments, of the wall of the left ventricle are contracted beforethe closure of the aortic valve. A negative minimum difference meansthat, although the temporal resynchronization has been improved, theventricular segments do not all contract before the closure of theaortic valve.

In the case of a fully implanted device, this adjustment test of AVD andVVD can be automatically repeated (e.g., weekly, monthly, etc.) to takeinto account possible changes of the patient's situation. Repeating theprocess illustrated in FIG. 7 may be useful to account for ventricularremodeling or for any other reason that would again provoke diastoliccontraction.

The diagnostic method described herein can be used in combination withalgorithms for automatic optimization of AVD and VVD such as thosedescribed in European Patent Application No. 2357020 A1 (Sorin CRM),which analyzes the typical sigmoid characteristic of variation of theAVD, and/or in the European Patent Application No. 1736203 A1 (SorinCRM) which evaluates an hemodynamic performance index as a function ofthe area enclosed by this characteristic. If the difference between thetiming values generated by the optimization algorithm (i.e., thealgorithm disclosed in the above-referenced patents) and the timingvalues generated by the present invention (i.e., the pair {AVD, VVD}that minimizes the temporal difference between the reference marker andthe contraction peak of the left ventricle) is negative or zero, thereis no proven temporal desynchronization and the values of AVD and VVDcalculated by the algorithm can be selected as optimal. However, if thisdifference is positive, the test of other values of AVD and VVD thanthose proposed by the optimization algorithm can improve the temporalresynchronization, with minimal impact on the spatial resynchronization.

What is claimed is:
 1. A device for evaluation and therapy of temporalventricular desynchronization in a patient, comprising: a plurality ofsensors collecting first data representative of a blood flow in a leftchamber of a heart and second data representative of a displacement of aleft ventricle of the heart; a processor coupled to the plurality ofsensors and the electrodes and configured to: receive the first data andthe second data from the plurality of sensors; determine a first timecorresponding to a closure of an aortic valve using the first data;detect a peak of contraction of the left ventricle using the seconddata; determine a second time corresponding to the peak of contractionof the left ventricle using the second data; calculate a temporal shiftbetween the second time corresponding to the peak of contraction of theleft ventricle and the first time corresponding to the closure of theaortic valve; select a current stimulation configuration from aplurality of predefined stimulation configurations based on thecalculated temporal shift; and generate stimulation pulses adapted to beapplied to electrodes adapted to be implanted in a right ventricularpacing site and a left ventricular pacing site according to the currentstimulation configuration.
 2. The device of claim 1, wherein the currentstimulation configuration comprises at least one of an inter-ventriculardelay or an atrioventricular delay and wherein the processor is furtherconfigured to adjust the current stimulation configuration by adjustingat least one of the inter-ventricular delay or the atrioventriculardelay to reduce the temporal shift.
 3. The device of claim 2, whereinadjusting at least one of the inter-ventricular delay or theatrioventricular delay comprises increasing at least one of theinter-ventricular delay or the atrioventricular delay if the second timeof the peak of contraction of the left ventricle is later than the firsttime of the closure of the aortic valve.
 4. The device of claim 1,wherein the plurality of sensors comprise a hemodynamic sensor, thehemodynamic sensor comprising at least one of: an implantable orexternal endocardial acceleration sensor, an implantable bioimpedancesensor, an implantable or external T wave detection sensor, or animplantable ventricular pressure sensor.
 5. The device of claim 1,wherein the plurality of sensors comprise a motion sensor, the motionsensor comprising at least one of: a motion sensor configured to beimplanted in an endocardial epicardial or endocoronary site, an externalmotion sensor, or a sensor for collection of a tomography field signal.6. The device of claim 1, wherein one of the plurality of sensors is animplantable sensor collecting an endocardial acceleration signal, andwherein the processor is further configured to determine the first timecorresponding to the closure of the aortic value by: determining anisovolumetric ventricular relaxation over a cardiac cycle between twosuccessive ventricular events using the first data; isolating acomponent in the endocardial acceleration signal corresponding to aportion of the cardiac cycle that includes a second peak of endocardialacceleration associated with the isovolumetric ventricular relaxation;and determining the first time as corresponding to a beginning of theisolated signal component.
 7. The device of claim 6, wherein theprocessor is further configured to determine the first time ascorresponding to the beginning of the isolated signal component by:determining, using the first data, when an energy envelope of theisolated signal component crosses a threshold value.
 8. The device ofclaim 1, wherein the plurality of sensors comprise at least two motionsensors that deliver signals representative of displacements of left andright ventricle walls of the myocardium, and wherein the processor isfurther configured to: determine fifth times of respective peaks ofcontraction of left and right ventricles based on the signalsrepresentative of the displacements of the left and right ventriclewalls, determine a temporal gap of the fifth times of the respectivepeaks of contraction of the left and right ventricles.
 9. The device ofclaim 8, wherein the current stimulation configuration comprises atleast one of the inter-ventricular delay or an atrioventricular delayand wherein the processor is further configured to adjust the currentstimulation configuration by adjusting at least one of theinter-ventricular delay or the atrioventricular delay to reduce thetemporal gap between the fifth times of the respective peaks ofcontraction of the left and right ventricles.
 10. The device of claim 1,wherein to determine the first time corresponding to the closure of theaortic valve, the processor is further configured to: determine anisovolumetric ventricular relaxation using the first data; identify aportion of an endocardial acceleration signal corresponding to a periodof endocardial acceleration associated with the isovolumetricventricular relaxation; and use a sixth time corresponding to abeginning of the identified portion of the endocardial accelerationsignal as the first time corresponding to the closure of the aorticvalve.
 11. A device for evaluation and therapy of temporal ventriculardesynchronization in a patient, comprising: a plurality of sensorscollecting first data representative of a blood flow in a left chamberof a heart and second data representative of a displacement of a leftventricle of the heart; a processor coupled to the plurality of sensorsand electrodes and configured to: determine a first time correspondingto a closure of an aortic valve using the first data; determine a peakof contraction of the left ventricle using the second data; determine asecond time corresponding to the peak of contraction of the leftventricle using the second data; calculate a temporal shift between thesecond time corresponding to the peak of contraction of the leftventricle and the first time corresponding to the closure of the aorticvalve; select a current stimulation configuration from a plurality ofpredefined stimulation configurations based on the calculated temporalshift; and generate stimulation pulses to be applied to electrodesadapted to be implanted in a right ventricular pacing site and a leftventricular pacing site according to the current stimulationconfiguration; wherein the processor is configured to determine thefirst time of closure of the aortic valve by: calculating an energyenvelope using an endocardial acceleration signal from the plurality ofsensors; identifying a third time at which a magnitude of the energyenvelope crosses a threshold energy value; and using the third time atwhich the magnitude of the energy envelope crosses the threshold energyvalue as the first time of closure of the aortic valve.
 12. A device forevaluation and therapy of temporal ventricular desynchronization in apatient, comprising: electrodes configured to be implanted in a rightventricular pacing site and a left ventricular pacing site; a processorconfigured to: determine a first time corresponding to a closure of anaortic valve and a second time corresponding to a peak of contraction ofa left ventricle of a heart using a measurement signal received from theelectrodes; calculate a temporal shift between the first time of closureof the aortic valve and the second time of the peak of contraction ofthe left ventricle; select a stimulation configuration from a pluralityof predefined stimulation configurations based on the calculatedtemporal shift; and cause stimulation pulses to be applied to theelectrodes according to the selected stimulation configuration.
 13. Thedevice of claim 12, wherein the stimulation configuration comprisesdelay values for at least one of an inter-ventricular delay or anatrioventricular delay.
 14. The device of claim 12, wherein theelectrode is an implantable hemodynamic sensor that measures a bloodflow in a left chamber of the heart and generates an endocardialacceleration signal, wherein the processor is configured to determinethe first time of closure of the aortic valve by: receiving theendocardial acceleration signal from the implantable hemodynamic sensor;determining an isovolumetric ventricular relaxation over a cardiac cyclebetween two successive ventricular events; identifying a portion of theendocardial acceleration signal corresponding to a period of endocardialacceleration associated with the isovolumetric ventricular relaxation;and determining the first time as corresponding to a beginning of theidentified portion of the endocardial acceleration signal.
 15. Thedevice of claim 12, wherein the electrode is an implantable hemodynamicsensor that measures a blood flow in a left chamber of the heart andgenerates an endocardial acceleration signal, wherein the processor isconfigured to determine the first time of closure of the aortic valveby: receiving the endocardial acceleration signal from the implantablehemodynamic sensor; calculating an energy envelope using the endocardialacceleration signal; and identifying the first time as corresponding toa magnitude of the energy envelope crosses a threshold energy value. 16.The device of claim 12, wherein the processor is further configured tocalculate a threshold energy value, wherein calculating the thresholdenergy value comprises: determining a maximum energy associated with anenergy envelope; identifying an energy value corresponding to apredetermined fraction of the maximum energy; and using the identifiedenergy value as the threshold energy value.
 17. The device of claim 12,wherein the electrode is a motion sensor configured to measure adisplacement of a left ventricle wall and generate a measurement signal,wherein the processor is configured to determine the second time of thepeak of contraction of the left ventricle by: receiving the measurementsignal from the motion sensor; and identifying the second time ascorresponding to when the measurement signal from the motion sensor isat an maximum.
 18. The device of claim 12, wherein the electrode is afirst motion sensor configured to measure displacement of a leftventricle wall and a second motion sensor configured to measuredisplacement of a right ventricle wall, wherein the processor is furtherconfigured to: receive measurement signals from the first motion sensorand the second motion sensor; determine the second time corresponding tothe peak of contraction of the left ventricle and an sixth timecorresponding to a peak of contraction of a right ventricle based on themeasurement signals; and identify a spatial desynchronization based on atemporal gap between the times of the peaks of contraction of the leftand right ventricles.
 19. The device of claim 18, wherein thestimulation configuration comprises at least one of an interventriculardelay or an atrioventricular delay and wherein the processor is furtherconfigured to adjust at least one of the interventricular delay or theatrioventricular delay to reduce the temporal gap between the times ofthe respective peaks of contraction of the left and right ventricles.20. The device of claim 12, wherein the electrode is an implantablehemodynamic sensor that measures a blood flow in a left chamber of theheart and generates an endocardial acceleration signal, wherein theprocessor is further configured to: receive the endocardial accelerationsignal from the implantable hemodynamic sensor; isolate in theendocardial acceleration signal a component corresponding to a secondpeak of endocardial acceleration associated with an isovolumetricventricular relaxation over a cardiac cycle between two successiveventricular events; and use a seventh time corresponding to a beginningof the isolated signal component as the first time of closure of theaortic valve.